Substance abuse (SA) affects up to 20% of the population at some point in their lives and exhibits a heritability rate between 40 and 60%. SA is likely due to complex genetics, i.e., multiple risk alleles of modest effect interacting with environmental factors to produce the addiction phenotype. Schizophrenia, which affects ~1% of the population and exhibits substantial heritability (~80%), is a disorder with a very high prevalence of SA. Nearly 90% of individuals with schizophrenia smoke cigarettes heavily, ~50% have ethanol dependence and high rates of stimulant abuse. Pharmacologic, post-mortem and recent genetic research have implicated NMDA receptors (NMDAR) in the pathophysiology of schizophrenia. NMDARs have also been implicated in the acquisition and extinction of SA in animal models. We hypothesize that the high prevalence of SA in schizophrenia is due to shared risk genes that disrupt NMDAR function. Specifically, 3 risk genes for schizophrenia affect the availability D-serine, a co-agonist at the NMDAR in cortico-limbic regions of the brain. We have developed mice, in which serine racemase, the enzyme that synthesizes D-serine has been genetically inactivated (SR-/- ). The SR-/- mice exhibit structural, neurochemical and behavioral homologies to schizophrenia. They also present abnormalities in the acquisition and extinction of conditioned hyperactivity to amphetamine, consistent with an increased vulnerability to SA. We will use SR-/- mice and, as positive controls, GlyT1+/- mice, which have increased NMDAR function, to assess the role of NMDAR function in two animal models of SA: the cocaine self-administration paradigm, which measures the reinforcing effects of cocaine and intracranial self-stimulation, which measures the propensity of the mouse to self-administer a rewarding brain stimulus, in essence the hedonic status of the subject. Alterations in the performance of SR-/- and GlyT1+/- mice on cocaine self- administration will be correlated with neuronal activity as monitored by cFos and DFosB expression in brain regions relevant to SA. Finally, we will determine whether behavioral abnormalities in the SR-/- mice can be reversed by treatments that replace the deficient D-serine.